title: Pb²⁺ induced IL-8 gene expression by extracellular signal-regulated kinases and the transcription factor, activator protein 1, in human gastric carcinoma cells.
abstract: Divalent lead (Pb(2+) ) is a common industrial pollutant epidemiologically associated with gastric cancers. Pb(2+) was found to promote tumorigenesis, which may include interleukin (IL)-8, a pro-inflammatory chemokine that promotes angiogenesis and tumor metastasis. Given that the gastrointestinal tract is a major route of Pb(2+) exposure, we investigated the ability of Pb(2+) to induce IL-8 expression in gastric carcinoma cells and its underlying mechanism. At a concentration of 0.1 μM, Pb(2+) induced IL-8 gene activation in gastric carcinoma AGS cells. Using a IL-8 promoter-deletion analysis, transcription factor activator protein 1 (AP-1) was identified as a necessary component of Pb(2+) -induced IL-8 gene activation. Upregulation of the IL-8 gene was abrogated by the MEK inhibitor, PD98059, and partially suppressed by the epidermal growth factor receptor inhibitors, AG1478 and PD153035. Furthermore, c-Jun protein expression was induced in cells treated with Pb(2+) , and overexpression of c-Jun enhanced Pb(2+) -induced IL-8 activation. Collectively, our findings highlight the pivotal roles of AP-1 and extracellular signal-regulated kinase in signal transduction of Pb(2+) -induced IL-8 gene activation. These molecules may be potential therapeutic targets for Pb(2+) -related inflammation leading to stomach carcinogenesis. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 315-322, 2015.
authors.affiliation: School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ying-Chi
authors.initials: YC
authors.lastname: Lin
authors.forename: Po-Li
authors.initials: PL
authors.lastname: Wei
authors.forename: Yao-Ting
authors.initials: YT
authors.lastname: Tsai
authors.forename: Jhen-Hong
authors.initials: JH
authors.lastname: Wong
authors.forename: Che-Mai
authors.initials: CM
authors.lastname: Chang
authors.forename: Jaw-Yuan
authors.initials: JY
authors.lastname: Wang
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Lee
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Chuang
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chang
mesh_terms: D045744:Cell Line, Tumor; D004785:Environmental Pollutants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics*; D007854:Lead / Q000633:toxicity*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D011799:Quinazolines / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016209:Interleukin-8; D016755:Proto-Oncogene Proteins c-jun; D011799:Quinazolines; D018808:Transcription Factor AP-1; D020032:Tyrphostins; C101044:RTKI cpd; D007854:Lead; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline
keywords: AP-1; ERK1/2; IL-8; MAPK; Pb2+; carcinogenesis